Page 323 - Read Online

Page 2 of 20 Varikuti et al. Vessel Plus 2020;4:28 I http://dx.doi.org/10.20517/2574-1209.2020.27

their contribution to pathogenesis in malaria, African sleeping sickness, Chagas disease, and leishmaniasis and
toxoplasmosis with an emphasis on their actions on the innate and adaptive immune mechanisms of resistance.

Keywords: Vascular endothelium, exosomes, leishmaniasis, malaria, trypanosomiasis, toxoplasmosis

INTRODUCTION
The vascular endothelium
The vascular endothelium (VE) is a large endocrine organ consisting of a single layer (one cell thick)
of endothelial cells (ECs). The VE mediates regulatory functions in cell proliferation, angiogenesis,
[1,2]
permeability, blood flow, thrombosis, thrombolysis, coagulation, homeostasis, and inflammation . It
also acts as the barrier between vascular and parenchymal compartments of all organs and regulates
the exchange of gases, immune cell trafficking, metabolism, and the spread of infections. The entire
circulatory system, from the heart to the smallest capillaries, is layered with ECs, which carry out
unique functions such as fluid filtration, maintaining the tone of the blood vessel, platelet and leukocyte
[3,4]
interactions, neutrophil recruitment, and hormone trafficking . The VE plays a major role in leukocyte
[5,6]
recruitment from the vessel lumen and transit into tissue parenchyma , and it is also the precursor for
[7]
both hematopoietic and endothelial lineages . The role of the VE is governed by the presence of many
membrane-bound receptors for molecules such as proteins, lipid transporting particles hormones, and
[8,9]
metabolites . Recent studies have identified the immunological role of the VE from the secretion of
cytokines and chemokines to the expression of adhesion molecules and antigen presentation [10-12] .
The VE is also involved in bacterial, viral, and protozoan infectious disease processes. However, the
interactions between the pathogen and the VE and how they both influence the disease outcome needs to
be explored further. A clearer understanding of these relationships may help in identifying potential targets
for therapeutic intervention(s) to prevent and/or reduce disease severity.

Role of the VE in innate immunity
The VE serves as the first line of defense against the physical stimuli and chemical agonists that are present
in the bloodstream during infection and disease by activating the inflammatory response when receptors
on the ECs, such as the toll-like receptors (TLRs) and NOD-like receptors (NLRs), recognize Pathogen
associated molecular patterns (PAMPs), damage associated molecular patterns (DAMPs), and pro-
inflammatory cytokines such as interleukin (IL)-1β or TNF-a [13,14] . These recognition signals regulate the
expression of pro-inflammatory genes (IL-1, IL-6, TNF-a, and IFN-g), leukocyte recruitment, phagocytosis,
and a subsequent adaptive immune response . During the early phase of an inflammatory response, ECs
[14]
are stimulated to release nitric oxide (NO), prostacyclin-2 (prostaglandin I2 or PGI ), and endothelin-1
2
to increase vasodilation by relaxing the surrounding smooth muscle cells [13,15] . Capillary permeability is
further facilitated by the removal of occludin between EC junctions and inflammatory mediators such as
kinins, cytokines, histamine, arachidonic acid, and complement components produced during this onset
[14]
of inflammation . VE activation upregulates expression of adhesion molecules such as intercellular
adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin by ECs to
aid chemokine-guided leukocyte rolling and extravasation through the vessel wall into the target site of the
tissue .
[14]
Role of the VE in adaptive immunity
The adaptive immune response can be mediated by the VE in multiple ways under certain conditions.
For example, thrombin-activated platelets as discussed above, upregulate CD40L similar to activated T
cells and are therefore able to interact with CD40 on the EC surface to promote cytokine and chemokine